US7759396B2 - Antineoplastic preparation and the use of antineoplastic preparation - Google Patents

Antineoplastic preparation and the use of antineoplastic preparation Download PDF

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Publication number
US7759396B2
US7759396B2 US11/813,526 US81352606A US7759396B2 US 7759396 B2 US7759396 B2 US 7759396B2 US 81352606 A US81352606 A US 81352606A US 7759396 B2 US7759396 B2 US 7759396B2
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Prior art keywords
cells
akg
alpha
glutamine
ketoglutarate
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US11/813,526
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US20080058422A1 (en
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Stefan Pierzynowski
Martyna Kandefer-Szerszen
Wojciech Rzeski
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SGP and Sons AB
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SGP and Sons AB
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Assigned to SGP & SONS AB reassignment SGP & SONS AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KANDEFER-SZERSZEN, MARTYNA, RZESKI, WOJCIECH, PIERZYNOWSKI, STEFAN
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • An object of the invention is antineoplastic preparation and the use of antineoplastic preparation.
  • the antineoplastic preparation distinguishes itself in that it contains alpha-ketoglutarate (AKG) or/and glutamine or/and glutamate or/and alpha-ketoglutarate of ornithine or/and dipeptides of glutamine and other amino acids or/and tripeptides of glutamine and other amino acids or/and di- and tripeptides of glutamate with other amino acid or/and mono- and divalent metal salts and other of alpha-keto-glutarate or/and glutamine or/and glutamate or/and ornithine of alpha-ketoglutarate.
  • AKG alpha-ketoglutarate
  • antineoplastic preparation is that the preparation containing alpha-ketoglutarate (AKG) or/and glutamine or/and glutamate or/and alpha-ketoglutarate of ornithine or and dipeptides of glutamine and other amino acids or/and tripeptides of glutamine and other amino acids or/and di- and tripeptides of glutamate with other amino acid or/and mono- and divalent metal salts and other of alpha-keto-glutarate or/and glutamine or/and glutamate or/and ornithine or alpha-ketoglutarate is used in the prophylaxis of neoplastic diseases.
  • AKG alpha-ketoglutarate
  • antineoplastic preparation is that the preparation containing alpha-ketoglutarate (AKG) or/and glutamine or/and glutamate or/and alpha-ketoglutarate of ornithine or/and dipeptides of glutamine and other amino acids or/and tripeptides of glutamine and other amino acids or/and di- and tripeptides of glutamate with other amino acid or/and mono- and divalent metal salts and other of alpha-keto-glutarate or/and glutamine or/and glutamate or/and ornithine of alpha-keto-glutarate is used for metastases inhibition.
  • alpha-ketoglutarate AKG
  • the preparation and the use of the preparation allows for the inhibition of the migration of neoplastic cells reflecting the potential role of AKG in the metastases inhibition.
  • the preparation added to the diet plays a role as neo-adjuvant supporting existing methods used in the neoplasm treatment. It may improve the quality of the a patient's life through the synergistic action with antineoplastic drugs and simultaneous protective activity to normal cells.
  • FIG. 1 depicts a curve presenting the proliferation of A549 cells with the stimulation by AKG.
  • FIG. 2 depicts the proliferation of C6 cells with AKG.
  • FIG. 3 depicts the proliferation of HT-29 cells with AKG stimulation.
  • FIG. 4 presents the proliferation of human neoplastic cells A549 in the presence of the cyclophosphamide with AKG.
  • FIG. 5 depicts the proliferation of human neoplastic cells A549 in the presence of iphosphamide with AKG.
  • FIG. 6 depicts the proliferation of human neoplastic cells A549 in the presence of thiotepa with AKG.
  • FIG. 7 depicts the inhibition of C6 cells migration due to AKG.
  • A549 human neoplastic cells of the lung cancer; the continuous line obtained from the Institute of the Immunology and the Experimental Therapy of Polish Academy of Science in Wroclaw.
  • HT-29 human neoplastic cells of the large intestine cancer; the continuous line obtained from the Institute of the Immunology and the Experimental Therapy of Polish Academy of Science in Wroclaw.
  • C6 the rat neoplastic cells of the brain cancer (glioma); the continuous line obtained from the Department of Neonatology, Humboldt University, Berlin, Germany.
  • DMEM:F-12 HAM 2:1
  • HT-29 and C6 cells on the basis DMEM.
  • 10% foetal beast serum (FBS), penicillin 100 i.u./ml and streptomycin 100 ⁇ g/ml were added.
  • the basis DMEM:F-12 HAM, DMEM was produced by Sigma company (Sigma, St. Louis, Mo., U.S.A.).
  • the foetal beast serum (FBS) was produced by Life Technologies company (Life Technologies, Düsseldorf, Germany). Remaining reagents were produced by Sigma company.
  • Cells stored in liquid nitrogen in a tissue bank were unfrozen at a temperature of 37° C., then poured into the plastic bottles containing the proper basis. They were cultured in a temperature of 37° C. in the incubator with 5% CO 2 flow. After the cells' reproduction liquid was poured out, the cells were washed with PBS (without the calcium and magnesium ions) and processed with 0.25% trypsin solution+EDTA to receive the suspension of cells necessary in the experience.
  • MTT solution in PBS condition in concentration 5 mg/ml was added into each pit on a plastic plate in a dose of 15 ⁇ l/pit. Plates were incubated for 3 hours at a temperature of 37° C. Thereafter, buffer SDS-HCl in a does 100 ⁇ l/pit was added and the plates were left at a temperature of 37° C. all night. The results were evaluated next day with the use of E-max Reader (Molecular Devices Corporation, Menlo Park, Calif., U.S.A.).
  • This method is for the estimation of the activity of substances affecting the mobility of cells in vitro. It is used in research on wounds healing, angiogenesis and neoplastic metastases.
  • C6 cells (1 ⁇ 10 6 ) suspended in the culture basis with the addition of 10% serum (FBS) were poured onto the culture plates (NUNC, Roskilde, Denmark) with 4 cm diameter.
  • FBS 10% serum
  • the flaw (wound) was done with the ending of automatic pipette and unstuck cells were removed by twice-rinsing the plates with a PBS solution.
  • AKG (10 and 20 mM) dissolved in the culture basis was added to the prepared culture. Plates were incubated for 24 hours in a temperature of 37° C. and in a humid atmosphere 95% air and 5% CO 2 . Thereafter the cultures were coloured with the May-Grünwald-Giemza method.
  • Antiproliferative activity of AKG in the cultures was estimated in differen kinds of neoplastic cells: the lung cancer cells (A549), the large intestine cancer cells (HT-29) and glioma cells (C6). Cells were processed with AKG in concentrations 0.5, 1, 2.5, 5, 10 and 20 mM, for 96 hours.
  • the examined substance has had antiproliferative activity with relation to all neoplastic cells types (see the diagram— FIG. 1 , FIG. 2 , FIG. 3 ).
  • Statistically significant (4.5%) inhibition of cells' growth was observed at AKG concentration 2.5 mM in A549 cell line in the comparison to the control group. That effect was correlated with a dose of AKG and was 7.8%, 12.4%, 17.5% with doses 5 mM, 10 mM and 20 mM respectively (see the diagram on FIG. 1 ).
  • the growth inhibition in glioma cells (C6) was 12.6% with AKG dose 2.5 mM, 7.9%—5 mM, 16%—10 mM and 19.8%—20 mM, respectively.
  • AKG increased its cytostatic activity by 6.4%, 9.8% and 14.4% respectively (the diagram— FIG. 4 ).
  • Iphosphamid 1.5 mM inhibited the cells growth by 7.3%.
  • AKG addition (5, 10 and 20 mM) that effect increased by 5%, 5.3% and 8.8% respectively (the diagram— FIG. 5 ).

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
US11/813,526 2005-01-11 2006-01-10 Antineoplastic preparation and the use of antineoplastic preparation Expired - Fee Related US7759396B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
PL372183 2005-01-11
PL372183A PL372183A1 (pl) 2005-01-11 2005-01-11 Preparat przeciwnowotworowy oraz zastosowanie preparatu przeciwnowotworowego
PLP372183 2005-01-11
PCT/PL2006/000003 WO2006075924A1 (en) 2005-01-11 2006-01-10 Antineoplastic preparation and the use of antineoplastic preparation

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US20080058422A1 US20080058422A1 (en) 2008-03-06
US7759396B2 true US7759396B2 (en) 2010-07-20

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US (1) US7759396B2 (pl)
EP (1) EP1845966B1 (pl)
JP (2) JP2008526838A (pl)
CN (1) CN101111241B (pl)
AT (1) ATE474570T1 (pl)
AU (1) AU2006205279B2 (pl)
CA (1) CA2593780C (pl)
DE (1) DE602006015608D1 (pl)
DK (1) DK1845966T3 (pl)
ES (1) ES2349233T3 (pl)
PL (2) PL372183A1 (pl)
WO (1) WO2006075924A1 (pl)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2033623A1 (en) * 2007-09-07 2009-03-11 Cutech S.R.L. Compositions comprising ornithine ketoglutarate (OKG)
WO2015123229A1 (en) * 2014-02-12 2015-08-20 The Regents Of The University Of California Compositions and methods for treating aging and age-related diseases and symptoms

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006551A (en) 1988-02-03 1991-04-09 Leopold & Co., Chem. Pharm. Fabrik Aktiengesellschaft Composition for destroying malignant tumors
US6429229B1 (en) * 1998-03-13 2002-08-06 Chiesi S.A. Keto acid salts and amine derivatives, and their use for preparing medicines
WO2004012662A2 (en) 2002-08-01 2004-02-12 Aesgen, Inc. Improved treatment of cancer with glutamine
WO2004098619A2 (en) * 2003-05-07 2004-11-18 Osteologix A/S Treating cartilage / bone conditions with water-soluble strontium salts
US20040259766A1 (en) * 2001-11-23 2004-12-23 Tadeusz Studzinski Use of glutamate, glutamate derivatives or metabolites, glutamate analogues or mixtures thereof for the manufacture of a composition for the treatment of osteoporosis
WO2006066244A2 (en) 2004-12-17 2006-06-22 Cash Alan B Method for extending lifespan and delaying the onset of age-related disease

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT412447B (de) * 2002-11-27 2005-03-25 C Y L Handelsges M B H Mittel mit zerstörender wirkung auf maligne tumore sowie verfahren zu seiner herstellung
US20050124684A1 (en) * 2003-08-29 2005-06-09 Ying Du 5-(hydroxymethyl) furfural and derivatives as inhibitors of TNFalpha and IL-1beta production

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006551A (en) 1988-02-03 1991-04-09 Leopold & Co., Chem. Pharm. Fabrik Aktiengesellschaft Composition for destroying malignant tumors
US6429229B1 (en) * 1998-03-13 2002-08-06 Chiesi S.A. Keto acid salts and amine derivatives, and their use for preparing medicines
US20040259766A1 (en) * 2001-11-23 2004-12-23 Tadeusz Studzinski Use of glutamate, glutamate derivatives or metabolites, glutamate analogues or mixtures thereof for the manufacture of a composition for the treatment of osteoporosis
WO2004012662A2 (en) 2002-08-01 2004-02-12 Aesgen, Inc. Improved treatment of cancer with glutamine
WO2004098619A2 (en) * 2003-05-07 2004-11-18 Osteologix A/S Treating cartilage / bone conditions with water-soluble strontium salts
WO2006066244A2 (en) 2004-12-17 2006-06-22 Cash Alan B Method for extending lifespan and delaying the onset of age-related disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Robinson et al. Amino acid nutrition and immune function in tumour-bearing rats . . . Clinical Science. 1999, vol. 97, pp. 657-669. *

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Publication number Publication date
CA2593780C (en) 2013-11-26
CN101111241A (zh) 2008-01-23
EP1845966B1 (en) 2010-07-21
JP2013035864A (ja) 2013-02-21
PL1845966T3 (pl) 2011-02-28
WO2006075924A1 (en) 2006-07-20
ATE474570T1 (de) 2010-08-15
CA2593780A1 (en) 2006-07-20
EP1845966A1 (en) 2007-10-24
ES2349233T3 (es) 2010-12-29
JP2008526838A (ja) 2008-07-24
AU2006205279B2 (en) 2011-05-26
AU2006205279A1 (en) 2006-07-20
PL372183A1 (pl) 2006-07-24
US20080058422A1 (en) 2008-03-06
CN101111241B (zh) 2010-12-01
DE602006015608D1 (de) 2010-09-02
DK1845966T3 (da) 2010-11-08

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